The central theme of this OAIC proposal is frailty, a syndrome of wasting and vulnerability characterized by the aggregate decline of a number of physiologic systems. This syndrome is predictive of the onset and progression of disability, falls and mortality in older adults. A primary recent focus of research in aging at Johns Hopkins has concerned the characterization and description of frailty, with the intent of developing a definition of the phenotype of frailty, whose ascertainment will prove useful to both clinicians and researchers. This fundamental research has laid the groundwork making possible research into the proximate molecular genetic mechanisms leading to frailty. Thus, the central goal of the Genetics Core is to provide the infrastructure and expertise in cutting-edge genomic technologies that will facilitate the elucidation of molecular and genetic contributors to frailty and training for investigators interested in aging and frailty research. This approach is expected to lead to three main outcomes. First, applying state of the art genetic and genomic methodologies in a variety of large study designs can be expected to identify genetic variants that contribute to specific physiologic components of frailty or to the syndrome of frailty itself. Second, incorporating genetic analyses in the study of frailty can be expected to further refine and improve phenotypic description and characterization of the frailty phenotype. Since many specific physiologic alterations, in the aggregate, likely contribute to frailty, genetic analysis can begin to identify specific important components of frailty arising from distinct causes. Third, interactions built into this proposal between geneticists, biostatisticians, genetic epidemiologists, and geriatricians, will facilitate the development of an analytical infrastructure that can be utilized to understand the role of the frailty syndrome in disease presentation and outcomes. Identifying the genetic causes or risk factors underlying frailty will directly lead to improved clinical research and treatments, whose aims would include the prevention and amelioration of the premature onset and progression of frailty associated with aging. With this knowledge and training, new and unique preventive and treatment strategies will follow that will help improve the quality of life of millions of older Americans.